Rheumatoid factors (RF) are autoantibodies that bind to one or more determinants on the Fc portion of IgG. RF are found not only in patients with rheumatoid arthritis (RA), but also in a variety of chronic infectious and inflammatory conditions and in elderly normal individuals. RF also constitute a high proportion of monoclonal antibodies produced by B cell tumors. Furthermore, RF are induced following immunization with a variety of bacterial antigens and may have a physiologic role in B cell regulation. Thus RF are unique autoantibodies because they have a physiologic role as well as being potentially pathogenic in patients with RA. I am using several approaches to understanding the genetic origins of RF. First, I wish to identify idiotypic determinants that are highly expressed on RF. This may yield important information about their molecular genetic origins. I have already generated an antiidiotypic antibody (4C9) that recognizes a shared determinant that is expressed on IgM RF in the serum of 34/43 RF positive patients with RA. I plan to determine whether particular idiotypes are expressed on RF from patients with autoimmune, malignant or infectious diseases. I also plan to generate antiidiotypic reagents to purified IgG RF. These antiidiotypes may identify determinants that are only present in RF patients and may yield information about determinants of pathogenicity. Using the ELISA spot assay, I will determine the frequencies of RF secreting B cells expressing RA associated idiotypes in both normal and RA individuals and determine the sites of RF production. I will generate idiotypic EBV transformed B cell lines in order to study the genes that encode RF. Using these B cell lines I hope to determine which V region genes can be used to encode idiotypic RF, whether IgM and IgG RF are encoded by the same genes and whether the same genes encode physiologic and pathologic RF.